The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.

https://jcp.bmj.com/content/jclinpath/55/4/244.full.pdf

The causal relation between human papillomavirus and cervical cancer

Summary We set out to estimate the age and genotype-specific prevalence of cervical human papillomavirus (HPV) DNA in women with normal cervical cytology worldwide by meta-analysis of a systematic literature review. Reports on HPV prevalence published between January, 1995, and January, 2005, were retrieved. To be included, studies required information on cervical cytology, plus detailed descriptions of study populations, methods used to collect cervical samples, and assays used for HPV DNA detection and typing. Final analyses included 78 studies that could be separated into women with normal cytology, and of which subsets of 44 and 48 studies had data on age and type-specific HPV prevalence, respectively. Overall HPV prevalence in 157 879 women with normal cervical cytology was estimated to be 10·4% (95% CI 10·2–10·7). Corresponding estimates by region were Africa 22·1% (20·9–23·4), Central America and Mexico 20·4% (19·3–21·4), northern America 11·3% (10·6–12·1), Europe 8·1% (7·8–8·4), and Asia 8·0% (7·5–8·4). In all world regions, HPV prevalence was highest in women younger than 35 years of age, decreasing in women of older age. In Africa, the Americas, and Europe, a clear second peak of HPV prevalence was observed in women aged 45 years or older. On the basis of these estimates, around 291 million women worldwide are carriers of HPV DNA, of whom 32% are infected with HPV16 or HPV18, or both. The HPV types most commonly detected are similar to those most commonly described in pre-neoplastic and cancer cases, although the relative contribution of HPV16 and HPV18 is substantially lower in cytologically normal women.

http://www.hu.ufsc.br/projeto_hpv/Worldwide%20prevalence%20and%20genotype%20distribution%20of%20cervical.pdf

Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis.

Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis.

HPVs (human papillomaviruses) infect epithelial cells and cause a variety of lesions ranging from common warts/verrucas to cervical neoplasia and cancer. Over 100 different HPV types have been identified so far, with a subset of these being classified as high risk. High-risk HPV DNA is found in almost all cervical cancers (>99.7%), with HPV16 being the most prevalent type in both low-grade disease and cervical neoplasia. Productive infection by high-risk HPV types is manifest as cervical flat warts or condyloma that shed infectious virions from their surface. Viral genomes are maintained as episomes in the basal layer, with viral gene expression being tightly controlled as the infected cells move towards the epithelial surface. The pattern of viral gene expression in low-grade cervical lesions resembles that seen in productive warts caused by other HPV types. High-grade neoplasia represents an abortive infection in which viral gene expression becomes deregulated, and the normal life cycle of the virus cannot be completed. Most cervical cancers arise within the cervical transformation zone at the squamous/columnar junction, and it has been suggested that this is a site where productive infection may be inefficiently supported. The high-risk E6 and E7 proteins drive cell proliferation through their association with PDZ domain proteins and Rb (retinoblastoma), and contribute to neoplastic progression, whereas E6-mediated p53 degradation prevents the normal repair of chance mutations in the cellular genome. Cancers usually arise in individuals who fail to resolve their infection and who retain oncogene expression for years or decades. In most individuals, immune regression eventually leads to clearance of the virus, or to its maintenance in a latent or asymptomatic state in the basal cells.

Molecular biology of human papillomavirus infection and cervical cancer.

The epidemiology of human papillomavirus infections.

The implementation of cytology based cervical screening programmes has reduced the incidence of cervical carcinoma world wide. Consequently, the development of improved cytological preparation methods such as liquid based cytology (LBC) and thin layer slide preparation has been welcomed. The addition of high risk human papillomavirus (HR-HPV) testing may further enhance the accuracy of screening programmes. Accumulating evidence suggests that detection of persistent infection with the same HR-HPV type would highlight individuals at greater risk of disease progression,1,2 yet the extent and importance of multiple HR-HPV infections in the progression of cervical neoplasia and its management remain unknown. To investigate these issues it is necessary to use genotyping methods that can track the persistence of specific HPV types and detect infections with multiple HR-HPV types.


“Accumulating evidence suggests that detection of persistent infection with the same high risk human papillomavirus (HR-HPV) type would highlight individuals at greater risk of disease progression, yet the extent and importance of multiple HR-HPV infections in the progression of cervical neoplasia and its management remain unknown”


A recent directive issued by the Scottish Executive has promoted the roll out of cervical LBC for use throughout primary care in Scotland. The residual material from LBC specimens is an ideal template for HPV testing. We have investigated the prevalence and diversity of HPV infection in a routine cervical screening population in Scotland using residual material from LBC specimens. The extent of multiple HPV infections was assessed and compared with cytological assessment of neoplasia. The results constitute the baseline data of a longitudinal study designed to investigate the impact of HPV detection, multiple HPV infection, and HPV type specific persistence on progression of cervical neoplasia.

https://jcp.bmj.com/content/jclinpath/57/1/68.full.pdf

Multiple high risk HPV infections are common in cervical neoplasia and young women in a cervical screening population.

Aims: To monitor the association between the course of high risk human papillomavirus (HR-HPV) infection and the development of cervical neoplasia over time, from a baseline of normal cervical cytology.

Methods: This paper presents the follow up data from a previous cross sectional analysis. Women from a screening population who had normal cytology and who were HR-HPV positive were recalled after two to three years for cytology and HPV genotyping. The development of cervical neoplasia at follow up was related to the course of HPV infection (clearance, persistence, or sequential infection) and the presence of single or multiple HPV infections at baseline. A comparator control group of women who were HPV and cytologically negative at baseline were selected from the same population.

Results: Twelve cases of dyskaryosis were found in women who were HPV positive at baseline; four were high grade. Only three cases of low grade dyskaryosis were found in the control group. Women with type specific persistent infections were significantly more likely to develop cervical neoplasia than women who cleared the infection (p = 0.0001) or were sequentially infected with different types (p = 0.001). Women with multiple HPV infections at baseline were no more likely to develop cervical dyskaryosis than those with a single infection.

Conclusions: Type specific persistent HR-HPV infection as monitored by genotyping can identify women at increased risk of cervical neoplasia more accurately than a single or repeated presence/absence HPV test. The cost effectiveness of such an approach should be investigated by an appropriate, large scale cost–benefit analysis.

https://jcp.bmj.com/content/jclinpath/58/9/946.full.pdf

Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study

Aims—To assess the validity and practicality of real time polymerase chain reaction (PCR) for human papillomavirus (HPV) testing in combination with liquid based cytology samples for cervical screening. Methods—Real time PCR using consensus (GP5+/6+) and type specific primers was developed to detect genital HPV types. This provides rapid, eYcient amplification followed by denaturation of the product and computer analysis of the kinetics data that are generated. Liquid based cytology samples were obtained from patients attending routine cervical screening clinics. DNA was extracted from the residual cellular suspension after cytology using spin columns. Results—Real time PCR successfully distinguished between HPV-16 and HPV-18

https://mp.bmj.com/content/molpath/54/1/24.full.pdf

M W Whitley

Papers

Multiple high risk HPV infections are common in cervical neoplasia and young women in a cervical screening population.

Persistent high risk HPV infection associated with development of cervical neoplasia in a prospective population study

Rapid real time PCR to distinguish between high risk human papillomavirus types 16 and 18